Biologically absorbable coatings for implantable devices and methods for fabricating the same

ABSTRACT

Coatings for an implantable medical device and a method of fabricating thereof are disclosed, the coatings comprising a biologically degradable, biologically erodable, and/or biologically resorbable ABA or AB block copolymer. A biologically active agent can be conjugated to the block copolymer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 11/641,250, filed on Dec. 18, 2006, issued as U.S. Pat. No.7,378,106, which is in turn a continuation of U.S. application Ser. No.10/630,261, filed on Jul. 30, 2003, issued as U.S. Pat. No. 7,169,404.The teaching of U.S. application Ser. No. 11/641,250, filed on Dec. 18,2006, is incorporated herein in its entirety by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to coatings for drug delivery devices, suchas drug eluting vascular stents, and methods for producing the same.

2. Description of the State of the Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the lumen wall. Theballoon is then deflated to a smaller profile to allow the catheter tobe withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings which can collapse and occludethe conduit after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalbypass operation. To reduce the partial or total occlusion of the arteryby the collapse of arterial lining and to reduce the chance of thedevelopment of thrombosis and restenosis, a stent is implanted in thelumen to maintain the vascular patency.

Stents are used not only as a mechanical intervention but also as avehicle for providing biological therapy. As a mechanical intervention,stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed, so that they can be inserted through smallvessels via catheters, and then expanded to a larger diameter once theyare at the desired location. Examples in patent literature disclosingstents which have been applied in PTCA procedures include stentsillustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No.4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued toWiktor.

Biological therapy can be achieved by medicating the stents. Medicatedstents provide for the local administration of a therapeutic substanceat the diseased site. In order to provide an efficacious concentrationto the treated site, systemic administration of such medication oftenproduces adverse or toxic side effects for the patient. Local deliveryis a preferred method of treatment in that smaller total levels ofmedication are administered in comparison to systemic dosages, but areconcentrated at a specific site. Local delivery thus produces fewer sideeffects and achieves more favorable results. One proposed method formedicating stents involves the use of a polymeric carrier coated ontothe surface of a stent. A solution which includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer.

Local administration of therapeutic agents via stents has shownfavorable results in reducing restenosis. However, there is a great needfor better and more effective coatings for local drug delivery.

SUMMARY

A medical article comprising an implantable substrate having a coatingis provided the coating includes an ABA or an AB block copolymer, theblock copolymer having moieties A and B, wherein one of the moietiesproduces a biological response and the other moiety provides the blockcopolymer with structural functionality. Examples of the biologicalmoiety include poly(alkylene glycols), poly(ethylene oxide),poly(ethylene oxide-co-propylene oxide), poly(N-vinyl pyrrolidone),poly(acrylamide methyl propane sulfonic acid) and salts thereof,sulfonated dextran, hyaluronic acid, heparin, or copolymers thereof.Examples of the structural moiety include poly(caprolactone),poly(butylene terephthalate), poly(ester amide), or copolymers thereof.The coating can include a biologically active agent incorporated intothe coating, and can include a biologically active agent conjugated tothe block copolymer. Examples of the biologically active agents that canbe conjugated to the ABA block copolymer include paclitaxel, antisenseagents, polyarginine, rapamycin and structural derivatives or functionalanalogs thereof, such as EVEROLIMUS, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,and sources of nitrogen oxide, such as diazenium diolates.

A medical article comprising an implantable substrate having a coatingis provided;

the coating includes phosphoryl choline or polyaspirin.

A method for fabricating a medical article is provided. The methodincludes applying a coating to at least a portion of an implantablesubstrate, the coating including an ABA or an AB block copolymer,wherein one of the moieties in the block copolymer produces a biologicalresponse and the other moiety provides the block copolymer withstructural functionality.

DETAILED DESCRIPTION 1. Terms and Definitions

The following definitions apply:

The terms “biologically degradable,” “biologically erodable,”“bioabsorbable,” and “bioresorbable” coatings and/or polymers aredefined as coatings and/or polymers that are capable of being completelydegraded and/or eroded when exposed to bodily fluids such as blood andare gradually resorbed, absorbed and/or eliminated by the body. Theprocesses of breaking down and eventual absorption and elimination ofthe coating and/or polymer can be caused, for example, by hydrolysis,metabolic processes, bulk or surface erosion, and the like.

Whenever the reference is made to “biologically degradable,”“biologically erodable,” “bioabsorbable,” and “bioresorbable” stentcoatings and/or polymers forming such stent coatings, it is understoodthat after the process of degradation, erosion, absorption, and/orresorption has been completed, no coating will remain on the stent.Whenever the terms “degradable,” “biodegradable,” or “biologicallydegradable” are used in this application, they are intended to broadlyinclude biologically degradable, biologically erodable, bioabsorbable,and bioresorbable coatings and/or polymers.

“Biodegradability,” “bioerodability,” “bioabsorbability,” and“bioresorbability” are defined as inherent properties of the coatingand/or polymer making the coating and/or polymer biologicallydegradable, biologically erodable, or biologically absorbable, andbiologically resorbable.

The term “biologically beneficial” refers to a biodegradable productthat brings about biological benefits to the patient as a result of thedegradation and absorption of the product by the patient's body.

“Fast release” is defined as in vivo release of substantially the entireamount of the drug from the stent coating in less than 15 days, forexample, within 7 to 14 days. “Slow release” is defined as in vivorelease of substantially the entire amount of the drug from the stentcoating in 15 days or longer, for example, within 15 to 56 days.

The terms “block copolymer” and “graft copolymer” are defined inaccordance with the terminology used by the International Union of Pureand Applied Chemistry (IUPAC). “Block copolymer” refers to a copolymercontaining a linear arrangement of blocks. The block is defined as aportion of a polymer molecule in which the monomeric units have at leastone constitutional or configurational feature absent from the adjacentportions. “Graft copolymer” refers to a polymer composed ofmacromolecules with one or more species of block connected to the mainchain as side chains, these side chains having constitutional orconfigurational features that differ from those in the main chain.

2. Embodiments of the Invention

A coating for an implantable medical device, such as a stent, accordingto embodiments of the present invention, can be a multi-layer structurethat can include the following four layers:

(a) a drug-polymer layer (also referred to as “reservoir” or “reservoirlayer”) or a polymer free drug layer;

(b) an optional primer layer;

(c) an optional topcoat layer; and/or

(d) an optional finishing coat layer.

Each layer of the stent coating can be formed on the stent by dissolvingthe polymer or a blend of polymers in a solvent, or a mixture ofsolvents, and applying the resulting polymer solution on the stent byspraying or immersing the stent in the solution. After the solution hasbeen applied onto the stent, the coating is dried by allowing thesolvent to evaporate. The process of drying can be accelerated if thedrying is conducted at an elevated temperature.

To incorporate a drug into the reservoir layer, the drug can be combinedwith the polymer solution that is applied onto the stent as describedabove. Alternatively, to fabricate a polymer free drug layer, the drugcan be dissolved in a suitable solvent or mixture of solvents, and theresulting drug solution can be applied on the stent by spraying orimmersing the stent in the drug solution. In one embodiment, thereservoir can optionally incorporate an additional active agent or drug,for example, by having the additional drug or active agent conjugated tothe polymer forming the reservoir layer.

Instead of introducing the drug as a solution, the drug can beintroduced as a colloid system, such as a suspension in an appropriatesolvent phase. To make the suspension, the drug can be dispersed in thesolvent phase using conventional techniques used in colloid chemistry.Depending on a variety of factors, e.g., the nature of the drug, thosehaving ordinary skill in the art can select the solvent to form thesolvent phase of the suspension, as well as the quantity of the drug tobe dispersed in the solvent phase. The suspension can be mixed with apolymer solution and the mixture can be applied on the stent asdescribed above. Alternatively, the drug suspension can be applied onthe stent without being mixed with the polymer solution.

The drug-polymer layer can be applied directly onto at least a part ofthe stent surface to serve as a reservoir for at least one active agentor a drug which is incorporated into the reservoir layer. The optionalprimer layer can be applied between the stent and the reservoir toimprove the adhesion of the drug-polymer layer to the stent. Theoptional topcoat layer can be applied over at least a portion of thereservoir layer and serves as a rate limiting membrane which helps tocontrol the rate of release of the drug. In one embodiment, the topcoatlayer can be essentially free from any active agents or drugs. Inanother embodiment, besides the active agent or drug contained in thereservoir layer, the topcoat can incorporate an additional active agentor drug, for example, by having the additional drug or active agentconjugated to the polymer forming the topcoat layer. If a topcoat layeris used, the optional finishing coat layer can be applied over at leasta portion of the topcoat layer for improving the biocompatibility of thecoating.

The process of the release of the drug from a coating having bothtopcoat and finishing coat layers includes at least three steps. First,the drug is absorbed by the polymer of the topcoat layer on thedrug-polymer layer/topcoat layer interface. Next, the drug diffusesthrough the topcoat layer using empty spaces between the macromoleculesof the topcoat layer polymer as pathways for migration. Next, the drugarrives to the topcoat layer/finishing layer interface. Finally, thedrug diffuses through the finishing coat layer in a similar fashion,arrives to the outer surface of the finishing coat layer, and desorbsfrom the outer surface. At this point, the drug is released into theblood stream. Consequently, a combination of the topcoat and finishingcoat layers, if used, can serve as a rate limiting barrier.

In one embodiment, any or all of the layers of the stent coating can bemade of a polymer that is biologically beneficial and biologicallydegradable, erodable, absorbable, and/or resorbable. In anotherembodiment, the outermost layer of the coating can be limited to such apolymer.

To illustrate in more detail, in the stent coating having all fourlayers described above (i.e., the primer, the reservoir layer, thetopcoat layer and the finishing coat layer), the outermost layer is thefinishing coat layer, which is made of a polymer that is biologicallybeneficial and biologically degradable, erodable, absorbable, and/orresorbable. In this case, optionally, the remaining layers (i.e., theprimer, the reservoir layer, the topcoat layer) can also be fabricatedfrom a polymer that is both biologically beneficial and biologicallydegradable; the polymer can be the same or different in each layer.

If the finishing coat layer is not used, the topcoat layer can becomethe outermost layer and is made of a polymer that is both biologicallybeneficial and biologically degradable. In this case, optionally, theremaining layers (i.e., the primer and the reservoir layer) can be alsofabricated of a polymer that is both biologically beneficial andbiologically degradable; and the polymer can be the same or different ineach of the four layers.

If neither the finishing coat layer nor the topcoat layer is used, thestent coating can have only two layers, the optional primer and thereservoir. The reservoir in this case is the outermost layer of thestent coating and is made of a polymer that is both biologicallybeneficial and biologically degradable. Optionally, the primer can bealso fabricated of a biologically degradable and biologically beneficialpolymer, which can be the same or different in the reservoir and in theprimer.

The biological degradation, erosion, absorption and/or resorption of abiologically degradable, erodable, absorbable and/or resorbable andbiologically beneficial polymer are expected to cause at least threeresults. First, the rate of release of the drug will increase due to thegradual disappearance of the polymer that forms the reservoir or thetopcoat layer, or both. By choosing an appropriate degradable polymer,the stent coating can be engineered to provide either fast or slowrelease of the drug, as desired. Those having ordinary skill in the artcan determine whether a stent coating having slow or fast release isadvisable for a particular drug. For example, fast release may berecommended for stent coatings loaded with antimigratory drugs, whichoften need to be released within 1 to 2 weeks. For antiproliferativedrugs, slow release may be needed (up to 30 days release time).

Second, if an additional active agent or drug is conjugated to thepolymer of the topcoat layer, that active agent or drug is expected tobe released as the polymer of the topcoat layer disappears as a resultof degradation, erosion, absorption and/or resorption, thus providingadditional therapeutic benefit. This embodiment is described in moredetailed later in this application.

Third, upon degradation of a biologically degradable, erodable,absorbable and/or resorbable polymer, which is at the same timebiologically beneficial, the products of degradation of the polymer canserve as other additional active agents which can be absorbed by thebody of the patient bringing about additional medical and biologicalbenefits.

Biologically degradable, erodable, absorbable and/or resorbable polymersthat are also biologically beneficial and that can be used for makingany of the stent coating layers, include block copolymers. Examples ofblock copolymers include ABA block copolymers, AB block copolymers orpolymers that are not necessarily block copolymers, as defined below,but still comprise ABA or AB blocks. Both ABA and AB block copolymerscontain a polymeric moiety A and a polymeric moiety B.

One way of describing the ABA block copolymers is by using the formula-[A-A-A]_(m)-[B-B-B]_(n)-[A-A-A]_(p)-, where each of “m,” “n,” and “p”is an integer greater than 0. The AB block copolymers can be describedby the formula -[A-A-A]_(m)-[B-B-B]_(n)-, where each of “m” and “n” isan integer greater than 0. The blocks of the ABA and AB block copolymersneed not be linked on the ends, since the values of the integersdetermining the number of A and B blocks ensure that the individualblocks are usually long enough to be considered polymers in their ownright. Accordingly, the ABA block copolymer can be namedpoly-A-block-co-poly-B-block-co-poly-A-block copolymer, and the AB blockcopolymer can be named poly-A-block-co-poly-B-block copolymer. Blocks“A” and “B,” typically larger than three-block size, can be alternatingor random. The values of “m” and “p” can be selected to have the blockcopolymer with the molecular weight of blocks A between about 300 andabout 40,000 Daltons, such as between about 8,000 and about 30,000Daltons, for example, about 15,000 Daltons. The values of “n” areselected to have the block copolymer with the molecular weight of blocksB between about 50,000 and about 250,000 Daltons, such as between about80,000 and about 200,000 Daltons, for example, about 100,000 Daltons.

In the ABA and AB block copolymers, one polymeric moiety can provide theblock copolymer with blood compatibility (“a biocompatible moiety”) andthe other polymeric moiety (“a structural moiety”) can provide the blockcopolymer with mechanical and adhesive properties that the blockcopolymer needs for making the stent coatings. In one embodiment, moietyA is the biocompatible moiety and moiety B is the structural moiety. Inanother embodiment, moiety A is the structural moiety and moiety B isthe biocompatible moiety. The biocompatible and the structural moietiesare selected to make the ABA and AB block copolymers biologicallydegradable. Examples of suitable biocompatible moieties includepoly(alkylene glycols), for example, poly(ethylene glycol) (PEG),poly(ethylene oxide), poly(propylene glycol) (PPG), poly(tetramethyleneglycol), poly(ethylene oxide-co-propylene oxide), poly(N-vinylpyrrolidone), poly(acrylamide methyl propane sulfonic acid) and saltsthereof (AMPS and salts thereof), poly(styrene sulfonate), sulfonateddextran, polyphosphazenes, poly(orthoesters), poly(tyrosine carbonate),hyaluronic acid, hyaluronic acid having a stearoyl or palmitoylsubstitutent group, copolymers of PEG with hyaluronic acid or withhyaluronic acid-stearoyl, or with hyaluronic acid-palmitoyl, heparin,copolymers of PEG with heparin, a graft copolymer of poly(L-lysine) andPEG, or copolymers thereof. A molecular weight of a suitablebiocompatible polymeric moiety can be below 40,000 Daltons to ensure therenal clearance of the compound, for example, between about 300 andabout 40,000 Daltons, more narrowly, between about 8,000 and about30,000 Daltons, for example, about 15,000 Daltons.

Examples of suitable structural moieties include poly(caprolactone)(PCL), poly(butylene terephthalate) (PBT), poly(ester amide), moietiescontaining butyl methacrylate fragments, moieties containing a laurylgroup, poly(lactic acid) (PLA), poly(aspirin), and copolymers thereof.Molecular weight of the blocks comprising the structural moiety can bebetween about 20,000 and about 250,000 Daltons, more narrowly, betweenabout 80,000 and about 200,000 Daltons, such as about 100,000 Daltons.

One example of the biodegradable ABA block copolymer is poly(ethyleneglycol)-block-poly(caprolactone)-block-poly(ethyleneglycol)(PEG-PCL-PEG). One possible structure of the PEG-PCL-PEG blockcopolymer is shown by formula (I):

In the PEG-PCL-PEG block copolymers shown by formula (I), the PEG blocksconstitute the biodegradable moiety, while the PCL block constitutes thestructural moiety. If desired, the positions of the moieties can beswitched to obtain a BAB block copolymer,poly(caprolactone)-block-poly(ethyleneglycol)-block-poly(caprolactone)(PCL-PEG-PCL). One possible structure ofthe PCL-PEG-PCL block copolymer is shown by formula (II):

Block copolymers shown by formulae (I) and (II) can be synthesized bystandard methods known to those having ordinary skill in the art, forexample, by acid- or based-catalyzed copolycondensation of PEG with PCL.Another example of a PEG-containing polyester, suitable for making astent and/or a stent coating in accordance with the present inventionincludes a block copolymer of PEG with PBT, such as poly(ethyleneglycol)-block-poly(butyleneterephthalate) (PEG-PBT), poly(ethyleneglycol)-block-poly(butylene terephthalate)-block-poly(ethylene glycol)(PEG-PBT-PEG). PEG-PBT-PEG block copolymer can be obtained, for example,by trans-esterification of dibutyleneterephthalate with PEG. Anotherexample of the PEG-containing polyester, suitable for making a stentand/or a stent coating in accordance with the present invention includesa block copolymer of PEG with PLA, such as poly(ethyleneglycol)-block-poly(lactic acid)-block-poly(ethylene glycol)(PEG-PLA-PEG). In PEG-PLA-PEG, the molecular weight of the units derivedfrom ethylene glycol can be between about 550 and about 30,000 Daltons,and the molecular weight of the units derived from lactic acid can bebetween about 20,000 and about 150,000 Daltons.

PEG-PBT and PEG-PBT-PEG block copolymers are known under a trade namePOLYACTIVE and are available from IsoTis Corp. of Holland. InPOLYACTIVE, the ratio between the units derived from ethylene glycol andthe units derived from butylene terephthalate can be between about0.67:1 and about 9:1. The molecular weight of the units derived fromethylene glycol can be between about 300 and about 4,000 Daltons, andthe molecular weight of the units derived from butylene terephthalatecan be between about 50,000 and about 250,000, for example, about100,000 Daltons.

Alternatively, if desired, the positions of the moieties in thePEG-PBT-PEG and PEG-PLA-PEG block copolymers can be switched to obtain aBAB block copolymers, poly(butyleneterephthalate)-block-poly(ethyleneglycol)-block-poly(butyleneterephthalate) (PBT-PEG-PBT) and poly(lacticacid)-block-poly(ethylene glycol)-block-poly(lactic acid) (PLA-PEG-PLA).

PEG-PCL-PEG, PCL-PEG-PCL, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT, PEG-PLA-PEGand PLA-PEG-PLA block copolymers all contain fragments with ester bonds.Ester bonds are known to be water-labile bonds. When in contact withslightly alkaline blood, ester bonds are subject to catalyzedhydrolysis, thus ensuring biological degradability of the blockcopolymer. One product of degradation of every block polymer, belongingto the group PEG-PCL-PEG, PCL-PEG-PCL, PEG-PBT, PEG-PBT-PEG,PBT-PEG-PBT, PEG-PLA-PEG and PLA-PEG-PLA is expected to be PEG, which ishighly biologically compatible. PEG also has an additional advantage ofbeing biologically beneficial, reducing smooth muscle cellsproliferation at the lesion site and thus capable of inhibitingrestenosis.

In one embodiment, instead of, or in addition to, the ABA blockcopolymers and/or AB block copolymers described above, compounds otherthan ABA block copolymers and/or AB block copolymers can be used formaking any layer of the stent coating, so long as these compounds areboth biologically degradable and biologically beneficial. Examples ofsuch compounds include polyaspirin and phosphoryl choline.

Any layer of the stent coating can contain any amount of thebiodegradable ABA or AB block copolymers described above, or a blend ofmore than one such copolymers. If less than 100% of the layer is made ofthe biodegradable ABA or AB block copolymer(s), other polymers cancomprise the balance. Examples of the alternative polymers that can beused include polyacrylates, such as poly(butyl methacrylate), poly(ethylmethacrylate), and poly(ethyl methacrylate-co-butyl methacrylate), andfluorinated polymers and/or copolymers, such as poly(vinylidenefluoride) and poly(vinylidene fluoride-co-hexafluoro propene),poly(N-vinyl pyrrolidone), poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters), polyalkyleneoxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen,cellulose, starch, collagen and hyaluronic acid), polyurethanes,silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, vinyl halide polymers and copolymers(such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methylether), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins, e.g., poly(ethylene-co-vinyl alcohol) (EVAL), ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers; polyamides (such as Nylon 66 andpolycaprolactam), alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, and carboxymethyl cellulose.

Representative examples of some solvents suitable for making the stentcoatings include N,N-dimethylacetamide (DMAC), N,N-dimethylformamide(DMF), tethrahydrofuran (THF), cyclohexanone, xylene, toluene, acetone,i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether,methyl butyl ketone, ethyl acetate, n-butyl acetate, and dioxane. Somesolvent mixtures can be used, as well. Representative examples of themixtures include:

(1) DMAC and methanol (e.g., a 50:50 by mass mixture);

(2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass mixture);

(3) i-propanol, and DMAC (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by massmixtures);

(5) acetone and xylene (e.g. a 50:50 by mass mixture);

(6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40 by massmixture); and

(7) 1,1,2-trichloroethane and chloroform (e.g., an 80:20 by massmixture).

FLUX REMOVER AMS is trade name of a solvent manufactured by Tech Spray,Inc. of Amarillo, Tex. comprising about 93.7% of a mixture of3,3-dichloro-1,1,1,2,2-pentafluoropropane and1,3-dichloro-1,1,2,2,3-pentafluoropropane, and the balance methanol,with trace amounts of nitromethane. Those having ordinary skill in theart will select a solvent or a mixture of solvents suitable for theparticular polymer being dissolved.

The therapeutic substance that can be used in the reservoir layer caninclude any substance capable of exerting a therapeutic or prophylacticeffect for a patient. The therapeutic substance may include smallmolecule substances, peptides, proteins, oligonucleotides, and the like.The therapeutic substance can be designed, for example, to inhibit theactivity of vascular smooth muscle cells. It can be directed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells to inhibit restenosis.

Examples of therapeutic substances that can be used includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., orCOSMEGEN® available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The active agent can also fall under the genus ofantineoplastic, anti-inflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g. TAXOTEREE®, from Aventis S. A.,Frankfurt, Germany) methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. ADRIAMYCIN®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. MUTAMYCIN®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as ANGIOMAX™ (bivalirudin, Biogen, Inc., Cambridge,Mass.). Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. CAPOTEN® and CAPOZIDE® from Bristol-Myers Squibb Co., Stamford,Conn.), cilazapril or lisinopril (e.g. PRINIVIL® and PRINZIDE® fromMerck & Co., Inc., Whitehouse Station, N.J.); calcium channel blockers(such as nifedipine), colchicine, fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name MEVACOR® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,genetically engineered epithelial cells, tacrolimus, dexamethasone, andrapamycin and structural derivatives or functional analogs thereof, suchas 40-O-(2-hydroxy)ethyl-rapamycin (known by the name of everolimus,available from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

As mentioned above, the drug(s) can be conjugated to the polymer, toform a drug-polymer adduct. The drug-polymer adduct can be then used formaking the reservoir and/or topcoat layer. In addition to the conjugateddrug, the coating can be also impregnated with the drug. For example,the drug-polymer adduct can be dissolved in a suitable solvent, or amixture of solvents, and the resulting solution of the drug-polymeradduct can be applied on the stent as described above.

The conjugated drug can include any substance capable of exerting atherapeutic or prophylactic effect in the practice of the presentinvention. Some examples of drugs that can be used for conjugation withthe ABA block copolymer include paclitaxel, antisense agents (e.g.,Rensten-NG), polyarginine (e.g., R7), rapamycin and structuralderivatives or functional analogs thereof, such as EVEROLIMUS,40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin,and molecules that are sources of nitrogen oxide (NO) such as diazeniumdiolates.

One method of conjugating an additional drug to the ABA block copolymeris by utilizing the reactive functional groups of the copolymer. Forinstance, when the ABA block copolymer is PEG-PCL-PEG, the terminalhydroxyls of the PEG blocks can be used for carrying out the process ofconjugating. Conjugating an additional drug to the ABA block copolymercan be illustrated by the process of binding diazenium diolate typenitric oxide donors to PEG-PCL-PEG.

Diazenium-diolate-type nitric oxide donors are adducts of nitric oxidewith nucleophilic amines. Diazenium diolates, also known as “NONOates,”are highly biologically compatible, and in slightly acidicmedia, theyspontaneously release NO. One example of diazenium diolate that can beused is spermine diazenium diolate (SDD).

SDD, also known by its chemical name as 1,3-propanediamine,N-{4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl}-diazen-1-ium-1,2-diolate,is an aliphatic NONOate having the formulaNH₂—(CH₂)₃—N[N⁺(O)N⁻—OH)]—(CH₂)₄—NH—(CH₂)₃—NH₂ and is available fromMolecular Probes, Inc. of Eugene, Oreg. Alternatively, otherdiazenium-diolate-type NO donors can be used. Some examples of thealternative diazenium-diolate-type NO donors that can be conjugated tothe PEG blocks of PEG-PCL-PEG include1-{N-methyl-N-[6-(N-methylammonio)hexyl]amino}diazen-1-ium-1,2-diolatehaving the formula CH₃—N⁺H₂—CH₂)₆—N(CH₃—N⁺(O⁻)═N—O⁻ (MAHMA-NO), andZ-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolatehaving the formula O—N⁺[N(CH₂CH₂NH₂)CH₂CH₂N⁺H₃]═N—O⁻ (DETA-NO). MAHMA-NOand DETA-NO can be obtained from Cayman Chemical Co. of Ann Arbor, Mich.

In order to carry out conjugation of SDD to a PEG-PCL-PEG blockcopolymer, the PEG block of the copolymer can be preliminarilyderivatized by tosylation (treatment with tosyl chloride), oralternatively by tresylation (by reacting with tresyl chloride). Tosylchloride is a derivative of toluene, para-toluenesulfonyl chloride,having the formula CH₃—C₆H₄—SO₂Cl (TsCl). The process of PEG-PCL-PEGderivatization can be conducted outside the stent or directly on thestent. The processes of tosylation or tresylation include an attack onthe terminal hydroxyl of the PEG block and can be illustrated byreactions (III) and (IV), respectively:

Alternatively, tresyl chloride (2,2,2-trifluoroethanesulphonyl chloride)can be used to derivatrize PEG-PCL-PEG, according to reaction scheme(IV) and tresyl group is attached to the PEG-PCL-PEG backbone viahydroxy group:

Next, tosylated or tresylated PEG-PCL-PEG can be modified by conjugatingSDD. Due to the presence of two primary and one secondary amino groups,SDD is readily conjugated to the tosylated or tresylated PEG-PCL-PEG viaalkylation of the amino groups. One possible process of conjugating canbe shown for tosylated PEG-PCL-PEG as reaction (V):

One or both PEG blocks of PEG-PCL-PEG can be modified with SDD accordingto the process described by reactions (III-V). Those having ordinaryskill in the art can determine under which conditions the two-stepprocess of conjugating SDD to PEG-PCL-PEG described by reactions (III-V)can be carried out. The resulting polymeric adduct can be describedschematically as Dz-PEG-PCL-PEG (one PEG block is modified) orDz-PEG-PCL-PEG-Dz (two PEG blocks are modified), where Dz is a fragmentderived from SDD.

The coatings and methods of the present invention have been describedwith reference to a stent, such as a balloon expandable orself-expandable stent. The use of the coating is not limited to stents,however, and the coating can be used with a variety of other medicaldevices. Examples of the implantable medical device that can be used inconjunction with the embodiments of this invention include stent-grafts,grafts (e.g., aortic grafts), artificial heart valves, cerebrospinalfluid shunts, pacemaker electrodes, axius coronary shunts andendocardial leads (e.g., FINELINE and ENDOTAK, available from GuidantCorporation). The underlying structure of the device can be of virtuallyany design. The device can be made of a metallic material or an alloysuch as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY),stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, tantalum-based alloys, nickel-titanium alloy, platinum,platinum-based alloys such as, e.g., platinum-iridium alloy, iridium,gold, magnesium, titanium, titanium-based alloys, zirconium-basedalloys, or combinations thereof. Devices made from bioabsorbable orbiostable polymers can also be used with the embodiments of the presentinvention.

“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from Standard Press Steel Co. ofJenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum.

3. Examples

The following examples are provided to further illustrate embodiments ofthe present invention.

Example 1

A first composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % poly(caprolactone) (PCL); and

(b) the balance DMAC solvent.

The first composition can be applied onto the surface of a bare 18 mmPENTA stent (available from Guidant Corporation) by spraying and driedto form a primer layer. A spray coater can be used having a 0.014 fannozzle maintained at about 60° C. with a feed pressure of about 0.2 atm(about 3 psi) and an atomization pressure of about 1.3 atm (about 20psi). About 70 μg of the wet coating can be applied. The primer can bebaked at about 60° C. for about 2 hours, yielding a dry primer layer.

A second composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PCL-PEG, where the molecular weight of each PEG block can beabout 10,000 Daltons, and the molecular weight of the PCL block can beabout 70,000 Daltons;

(b) between about 0.05 mass % and about 2.0 mass %, for example, about1.0 mass % paclitaxel; and

(c) the balance DMAC solvent.

The second composition can contain about 300 μg PEG-PCL-PEG and about200 μg paclitaxel. The second composition can be applied onto the driedprimer layer to form the reservoir layer, using the same sprayingtechnique and equipment used for applying the primer layer, followed bydrying, e.g., by baking as described above.

A third composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PCL-PEG;

(b) the balance the DMAC solvent.

The third composition can be applied onto the dried reservoir layer toform a topcoat layer, using the same spraying technique and equipmentused for applying the primer layer and the reservoir layer. About 200 μgof the wet coating can be applied, followed by drying, e.g., by bakingas described above.

Example 2

The primer layer can be applied on a stent as described in Example 1.

A composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PCL-PEG;

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PCL;

(c) between about 0.05 mass % and about 2.0 mass %, for example, about1.0 mass % paclitaxel; and

(c) the balance DMAC solvent.

The composition can contain about 200 μg PEG-PCL-PEG, about 100 μg PCL,and about 200 μg paclitaxel. The composition can be applied onto thedried primer layer to form the reservoir layer, using the same sprayingtechnique and equipment used for applying the primer layer, followed bydrying, e.g., by baking as described above.

Example 3

The stent can be coated as described in Example 1, but instead of thetopcoat layer that comprises PEG-PCL-PEG, the topcoat layer can be madeof a Dz-PEG-PCL-PEG-Dz adduct.

Example 4

The stent can be coated as described in Example 1. A composition can beprepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % polyaspirin;

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % EVEROLIMUS; and

(c) the balance DMAC solvent.

The composition can contain about 150 μg polyaspirin, and about 100 μgEVEROLIMUS. The composition can be applied onto the dried topcoat layerto form the finishing coat layer, using the same spraying technique andequipment used for applying the primer layer, followed by drying, e.g.,by baking as described above.

Example 5

The stent can be coated as described in Example 1, but instead of areservoir layer that comprises paclitaxel, the reservoir layer caninclude EVEROLIMUS.

Example 6

A first composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT; and

(b) the balance a solvent blend comprising 1,1,2-trichloroethane andchloroform in a mass ratio between about 4:1.

The brand of PEG-PBT that can be used can have about 45 molar % PBTunits and about 55 molar % PEG units. The molecular weight of the PEGunits can be about 300 Daltons, and the molecular weight of the PBTblocks can be about 100,000 Daltons. The first composition can beapplied onto the surface of a bare 18 mm PENTA stent to form a primerlayer as described in Example 1. The primer can contain about 70 μgPEG-PBT.

After the primer layer has been formed, a reservoir layer comprisingthree sub-layers can be formed according to the following procedure. Asecond composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % poly(L-arginine) R7; and

(b) the balance a solvent blend containing methanol and water in a massratio of about 3:1.

The second composition can be applied over the primer layer usingtechniques described above, and dried, e.g., by baking, to form a firstreservoir sub-layer.

A third composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % hyaluronic acid; and

(b) the balance a solvent blend containing ethanol and water in a massratio of about 3:1.

The third composition can be applied over the first reservoir sub-layerusing techniques described above, and dried, e.g., by baking, to form asecond reservoir sub-layer.

A fourth composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 3.0mass % PEG-PBT; and

(b) the balance a solvent blend of 1,1,2-trichloroethane and chloroformdescribed above.

The brand of PEG-PBT that can be used can have about 30 molar % PBTunits and about 70 molar % PEG units. The molecular weight of the PEGblocks can be about 1,000 Daltons, and the molecular weight of the PBTblocks can be about 100,000 Daltons. The fourth composition can beapplied over the second reservoir sub-layer using techniques describedabove, and dried, e.g., by baking to complete formation of the reservoirlayer by forming a third reservoir sub-layer. The overall reservoirlayer can contain about 300 μg R7, about 200 μg hyaluronic acid, andabout 300 μg PEG-PBT.

A fifth composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 20 molar % PBT units and about 80 molar %PEG units (The molecular weight of the PEG units can be about 4,000Daltons);

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % an adduct of the same brand of PEG-PBT with hyaluronic acid; and

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The PEG-PBT-hyaluronic acid adduct can be synthesized by esterificationof PEG-PBT with hyaluronic acid with a mass ratio between PEG-PBT andhyaluronic acid of about 2:1. Those having ordinary skill in the art candetermine the conditions under which the esterification can be carriedout.

The fifth composition can be applied onto the dried reservoir layer toform a topcoat layer using the same spraying and drying techniques, asdescribed above. The topcoat layer can contain about 200 μg PEG-PBT andabout 100 μg hyaluronic acid.

Example 7

A first composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % a silk-elastin protein block copolymer; and

(b) the balance DMAC solvent.

Silk-elastin protein block copolymers combine repeating blocks of aminoacids providing the copolymer with the mechanical strengthcharacterizing silk and the flexibility characterizing elastin.Silk-elastin block copolymer can be obtained from Protein PolymerTechnologies, Inc. of San Diego, Calif. The first composition can beapplied onto the surface of a bare 18 mm PENTA stent to form a primerlayer as described in Example 1. The primer can contain about 70 μgsilk-elastin.

After the primer layer has been formed, a reservoir layer comprising twosub-layers can be formed according to the following procedure. A secondcomposition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % poly(L-arginine) R7; and

(b) the balance a solvent blend containing methanol and water in a massratio of about 3:1.

The second composition can be applied over the primer layer usingtechniques described above, and dried, e.g., by baking, to form a firstreservoir sub-layer.

A third composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % hyaluronic acid;

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % silk-elastin; and

(c) the balance a solvent blend containing methanol and water in a massratio of about 3:1.

The third composition can be applied over the first reservoir sub-layerusing techniques described above, and dried, e.g., by baking, tocomplete formation of the reservoir layer by forming a second reservoirsub-layer. The overall reservoir layer can contain about 100 μg R7,about 100 μg hyaluronic acid, and about 100 μg silk-elastin.

A fourth composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % silk-elastin; and

(b) the balance a solvent blend containing methanol and water in a massratio of about 3:1.

The fourth composition can be applied over the reservoir layer usingtechniques described above, and dried, e.g., by baking to form anintermediate layer. The intermediate layer can contain about 50 μgsilk-elastin.

A fifth composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 20 molar % PBT units and about 80 molar %PEG units. The molecular weight of the PEG units can be about 4,000Daltons;

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 45 molar % PBT units and about 55 molar %PEG units. The molecular weight of the PEG units can be about 300Daltons; and

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The fifth composition can be applied onto the dried reservoir layer toform the topcoat layer using the same spraying and drying techniques, asdescribed above. The topcoat layer can then be annealed by heating toabout 80° C. for about 30 minutes and then to about 50° C. for about 1hour. The topcoat layer can contain about 100 μg of each kind ofPEG-PBT.

Example 8

A stent can be coated with a primer layer as described in Example 6. Afirst composition can be prepared, comprising:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 45 molar % PBT units and about 55 molar %PEG units. The molecular weight of the PEG units can be about 300Daltons;

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % EVEROLIMUS;

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The composition can contain about 100 μg PEG-PBT, and about 100 μgEVEROLIMUS. The composition can be applied onto the dried primer layerto form the reservoir layer using the same spraying technique andequipment used for applying the primer layer, followed by drying, e.g.,by baking as described above.

A second composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT; and

(b) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The same kind of PEG-PBT as the one used for making the reservoir layercan be used. The second composition can be applied over the reservoirlayer using techniques described above, and dried, e.g., by baking, toform an intermediate layer. The intermediate layer can contain about 70μg PEG-PBT. The reservoir layer/the intermediate layer sequence can berepeated 4 times to achieve a total EVEROLIMUS load of about 400 μg.

Following formation of the reservoir layer/intermediate layer system,the topcoat layer can be formed as described in Example 7.

Example 9

A stent can be coated with a primer layer as described in Example 6. Afirst composition can be prepared, comprising:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 45 molar % PBT units and about 55 molar %PEG units (The molecular weight of the PEG units can be about 300Daltons);

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % EVEROLIMUS;

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The composition can contain about 100 μg PEG-PBT and about 100 μgEVEROLIMUS. The composition can be applied onto the dried primer layerto form a reservoir layer using the same spraying technique andequipment used for applying the primer layer, followed by drying, e.g.,by-baking, as described above.

A second composition can be prepared, comprising:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 45 molar % PBT units and about 55 molar %PEG units (The molecular weight of the PEG units can be about 300Daltons);

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % polyaspirin; and

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The second composition can be applied over the reservoir layer usingtechniques described above, and dried, e.g., by baking, to form anintermediate layer. The intermediate layer can contain about 50 μgPEG-PBT and about 50 μg polyaspirin. The reservoir layer/intermediatelayer sequence can be repeated 4 times to achieve a total EVEROLIMUSload of about 400 μg and a total polyaspirin load of about 200 μg.

A third composition can be prepared by mixing the following components:

(a) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % PEG-PBT having about 45 molar % PBT units and about 55 molar %PEG units (The molecular weight of the PEG units can be about 300Daltons);

(b) between about 1.0 mass % and about 15 mass %, for example, about 2.0mass % polyaspirin; and

(c) the balance the blend of 1,1,2-trichloroethane and chloroformdescribed above.

The third composition can be applied onto the dried reservoirlayer/intermediate layer system to form a topcoat layer using the samespraying and drying techniques as described above. The topcoat layer canthen be annealed by being heated to about 80° C. for about 30 minutesand then to about 50° C. for about 1 hour. The topcoat layer can containabout 100 μg PEG-PBT and about 200 μg polyaspirin.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A medical article comprising an implantable substrate comprising acoating, the coating comprising an ABA or an AB block copolymer and abiologically active agent conjugated to the copolymer, the blockcopolymer having A and B blocks, wherein one of the blocks comprises abiocompatible moiety and the other block comprises a structural moietythat provides the block copolymer with structural functionality, whereinthe structural moiety comprises polycaprolactone or copolymers thereofand the structural moiety has a molecular weight of about 80,000 toabout 200,000 Daltons, and wherein the biologically active agent isselected from the group consisting of paclitaxel, polyarginine,rapamycin, derivatives and analogs of rapamycin, and combinationsthereof.
 2. The medical article of claim 1, wherein the medical articleis a stent.
 3. The medical article of claim 1, wherein block A comprisesthe biocompatible moiety, and block B comprises the structural moiety.4. The medical article of claim 1, wherein block B comprises thebiocompatible moiety, and block A comprises the structural moiety. 5.The medical article of claim 1, wherein the biocompatible moiety isselected from the group consisting of poly(alkylene glycols),poly(ethylene oxide), poly(ethylene oxide-co-propylene oxide),poly(N-vinyl pyrrolidone), poly(acrylamide methyl propane sulfonic acid)and salts thereof, sulfonated dextran, polyphosphazenes,poly(orthoesters), poly(tyrosine carbonate), hyaluronic acid, hyaluronicacid having a stearoyl or palmitoyl substituent group, poly(ethyleneglycol)-hyaluronic acid, poly(ethylene glycol)-hyaluronic acid-stearoyl,poly(ethylene glycol)-hyaluronic acid-palmitoyl, heparin, poly(ethyleneglycol)-heparin, and copolymers thereof.
 6. The medical article of claim5, wherein the poly(alkylene glycol) is selected from the groupconsisting of poly(ethylene glycol), polypropylene glycol),poly(tetramethylene glycol), a graft copolymer of poly(L-lysine) andpoly(ethylene glycol), and copolymers thereof.
 7. The medical article ofclaim 1, additionally comprising an additional biologically active agentincorporated into the coating.
 8. The medical article of claim 1,wherein the derivative or analog of rapamycin is selected from the groupconsisting of everolimus, 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, andcombinations thereof.
 9. The medical article of claim 1, wherein theblock copolymer comprises blocks of poly(ethylene glycol) (PEG) andpolycaprolactone (PCL) and the block copolymer is of a formula I or II:

wherein m, n, and p are independent integers greater than 0, wherein thePEG block has a molecular weight between about 300 and about 40,000Daltons, and wherein the PCL block has a molecular weight between about80,000 and about 200,000 Daltons.
 10. A medical article comprising animplantable substrate comprising a coating, the coating comprising anABA or an AB block copolymer and diazenium diolate conjugated to theblock copolymer, the block copolymer having A and B blocks, wherein oneof the blocks comprises a biocompatible moiety and the other blockcomprises a structural moiety that provides the block copolymer withstructural functionality and the structural moiety is of a molecularweight of about 80,000 to about 200,000 Daltons, and wherein thestructural moiety comprises polycaprolactone or copolymers thereof. 11.The medical article of claim 10, wherein the block copolymer comprisesblocks of poly(ethylene glycol) (PEG) and polycaprolactone (PCL) and theblock copolymer is of a formula I or II:

wherein m, n, and p are independent integers greater than 0, wherein thePEG block has a molecular weight between about 300 and about 40,000Daltons, and wherein the PCL block has a molecular weight between about80,000 and about 200,000 Daltons.